CASE REPORT published: 18 June 2021 doi: 10.3389/fonc.2021.673877

Case Report: Nintedanib for Pembrolizumab-Related Pneumonitis in a Patient With Non-Small Cell Lung Cancer

† † Xiao-Hong Xie , Hai-Yi Deng , Xin-Qing Lin, Jian-Hui Wu, Ming Liu, Zhan-Hong Xie, Yin-Yin Qin and Cheng-Zhi Zhou*

State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China

Pembrolizumab, an immune checkpoint inhibitor (ICI) approved for advanced non-small cell lung cancer (NSCLC) treatment, has shown superior survival benefits. However, Edited by: pembrolizumab may lead to severe immune-related adverse events (irAEs), such as Nathaniel Edward Bennett Saidu, INSERM U1016 Institut Cochin, checkpoint inhibitor-related pneumonitis (CIP). The routine treatment of CIP was based on France systemic corticosteroids, but the therapies are limited for patients who are unsuitable for Reviewed by: steroid therapy. Here, we present the first successful treatment of nintedanib for Luc Cabel, pembrolizumab-related pneumonitis in a patient with advanced NSCLC. Institut Curie, France Lorenzo Lovino, Keywords: checkpoint inhibitor-related pneumonitis, nintedanib, steroid therapy, non-small cell lung University of Pisa, Italy cancer, pembrolizumab *Correspondence: Cheng-Zhi Zhou [email protected] † INTRODUCTION These authors have contributed equally to this work Introduction of immune checkpoint inhibitor (ICI) therapy leads to a significant survival improvement invarioustumors(1). Pembrolizumab has been found to be superior to other chemotherapeutic agents Specialty section: as first-line treatment in metastatic non-small cell lung cancer (NSCLC) (2). However, pembrolizumab This article was submitted to Pharmacology of may lead to severe immune-related adverse events (irAEs), such as checkpoint inhibitor-related Anti-Cancer Drugs, pneumonitis (CIP) (3). The real-world incidence of CIP in patients with NSCLC is reported up to a section of the journal 19% for all grades (4), and the routine treatment of CIP is based on systemic corticosteroids. However, Frontiers in Oncology the optional therapies are limited if patients are not sensitive to steroid therapy. Received: 28 February 2021 Nintedanib, an oral tyrosine kinase inhibitor, has been approved for slowing progression of idiopathic Accepted: 28 May 2021 pulmonary fibrosis (IPF) (5). Nintedanib blocks the vascular endothelial growth factor (VEGF), the Published: 18 June 2021 platelet-derived growth factor receptor (PDGF) and the fibroblast growth factor receptor (FGFR). All Citation: these receptors are involved in cancer development, therefore nintedanib is considered to possess an Xie X-H, Deng H-Y, Lin X-Q, antitumor effect (6). For instance, nintedanib in combination with docetaxel acts as the second-line Wu J-H, Liu M, Xie Z-H, Qin Y-Y therapy for advanced NSCLC (7). Nintedanib plus paclitaxel may improve PD-L1 treatment for and Zhou C-Z (2021) Case Report: metastatic triple negative breast cancer (8). Two studies have given clues that nintedanib may prevent Nintedanib for Pembrolizumab- anticancer therapy-related pneumonitis. Fang et al. found that nintedanib has a dramatic effect on Related Pneumonitis in a Patient With Non-Small Cell Lung Cancer. targeted therapy-related interstitial pneumonia, providing a promising strategy for the patients who are Front. Oncol. 11:673877. not suitable for corticosteroid therapy (9). Unlike targeted therapy-associated pneumonitis, CIP may be doi: 10.3389/fonc.2021.673877 caused by excessive autoimmune response of tumor infiltrating lymphocytes (10). Interestingly,

Frontiers in Oncology | www.frontiersin.org 1 June 2021 | Volume 11 | Article 673877 Xie et al. Case Report: CIP Treated Successfully With Nintedanib

Yamakawa and colleagues reported that the addition of nintedanib complained of fever (38.4°C) and shortness of breath. to prednisolone prevented atezolizumab-induced pneumonitis in Pembrolizumab was discontinued and oxygen inhalation was IPF combined with NSCLC (11). It is worth noting that as an required. After receiving methylprednisolone (80 mg/day) for a immunosuppressor, VEGF may function by inhibiting dendric week, he reported no significant symptom alleviation. Therefore, cells (DCs) maturation and immigration, along with promoting he was transferred immediately to our hospital. On admission, he PD-L1 expression by DCs. Since nintedanib can target the VEGF presented with acute dyspnea. His blood pressure was normal, but pathway, we assume it may prevent ICI-induced pneumonitis. his blood oxygen saturation was 96%. Laboratory tests revealed the Here, we present a successful treatment of nintedanib for serum tumor markers were within the normal range except for pembrolizumab-related pneumonitis in a patient with elevated Krebs von den Lungen-6 (KL-6) (1575 U/mL), and no advanced NSCLC. abnormalities in white blood cell count, lactate dehydrogenase and C-reactive protein. A repeat chest CT scan showed multiple patchy and striped shadows in the left lung on July 24 (Figures 1C–E), CASE PRESENTATION and stable disease (RECIST criteria) of primary tumor lesion was evaluated. Pulmonary function tests indicated restrictive A 58-year-old man was sent to a local hospital with shortness of ventilatory defect. Microbiological testing of bronchoalveolar breath. He denied any history of chronic pulmonary diseases. lavage fluid were negative (including staining and culture for However, chest computed tomography (CT) scan in May 2020 bacteria, fungi, viruses, mycobacteria). The diagnosis of grade 3 showed a mass in the upper lobe of the right lung (Figures 1A, B). pembrolizumab-related pneumonitis was based on the above The patient was diagnosed with lung adenocarcinoma with bone findings. The initial dosage of methylprednisolone (80mg/day) metastasis after a thorough work-up, and the pathological did not improve his clinical symptoms and we decided to deliver examination revealed it to be driver gene-negative. He strongly him with methylprednisolone (40 mg/day) and added nintedanib refused chemotherapy and insisted to receive immunotherapy. He (150 mg bid) to CIP treatment. Five days later, his clinical was then administered 100 mg of pembrolizumab (2 mg/kg, every condition greatly improved, with obvious radiological 3 weeks) combined with bevacizumab by the local physician on improvement in the left lung and stable primary tumor lesion May 17, 2020. After the third pembrolizumab infusion, he on follow-up CT (Figures 1F–H). Since we were concerned about

FIGURE 1 | Development of ICI-related pneumonitis in a patient treated with pembrolizumab for lung adenocarcinoma. (A, B) Chest CT images showed the lesions in the upper lobe of the right lung before treatment (May 17, 2020). (C–E) After 3 cycles of immunotherapy, CT images showed that primary lesions were stabilized, but pneumonitis in the left lung (July 24, 2020). (F–H) CT images showed obvious improvement of pneumonitis (July 29, 2020).

Frontiers in Oncology | www.frontiersin.org 2 June 2021 | Volume 11 | Article 673877 Xie et al. Case Report: CIP Treated Successfully With Nintedanib the side effects of corticosteroids, we tried to lower the dose of pembrolizumab plus bevacizumab as first-line treatment for methylprednisolone to 20 mg/day, but nintedanib (150 mg bid) NSCLC. The anti-VEGF effect of nintedanib can only partially was continued. After 2 weeks of nintedanib monotherapy, the explain its prophylaxis for refractory CIP because bevacizumab patient’s condition improved so he withdrew nintedanib. (an anti VEGF antibody) does not have this effect on CIP. Unfortunately, he experienced rapid metastatic progression and Besides VEGFR family, nintedanib targets pro-angiogenic and died 2 months later. pro-fibrotic pathways mediated by PDGFR, FGFR and as well as Src and Flt-3 kinases, which are related to the pathogenesis of pulmonary fibrosis. Nintedanib competitively binds to the ATP DISCUSSION of these receptors, blocking the proliferation, migration, and signaling transduction of fibroblasts, which might prevent CIP. The patient developed CIP after the third injection of VEGF inhibition can enhance immunotherapy benefitfora pembrolizumab. According to radiographic classification, this variety of cancers (18). We think that the local physician had the case is interstitial pneumonia (12). Laboratory test showed that hypothesis that concurrent VEGF blockade may enhance the anti- his serum KL-6 was markedly increased. KL-6 is regarded as an tumor activity of pembrolizumab for NSCLC patients. However, important biomarker for interstitial lung disease (ILD) and stable disease of primary tumor lesion was evaluated on his chest classified as MUC1 mucin protein, and regenerating type II CT after three cycles of pembrolizumab plus bevacizumab. During pneumocytes are the primary cellular source of KL-6/MUC1 in CIP, pembrolizumab was stopped, but nintedanib was continued. the affected lungs of patients with ILD. Serum KL-6/MUC1 is If nintedanib and PD1 immunotherapy would be administered to elevated in 70% to 100% of patients with various ILDs such as the patient with NSCLC, will the combination therapy have both idiopathic interstitial pneumonias, radiation pneumonitis, drug- anticancer efficacy and prophylaxis for CIP? At the moment, we induced ILD and acute respiratory distress syndrome (13). have insufficient experience in the use of nintedanib, but it seems Clinicians should be fully aware of the possibility of ICI-induced that nintedanib should be used at an earlier onset of CIP. pulmonary toxicity when using programmed death-1/programmed In conclusion, nintedanib combined with corticosteroid death-ligand 1 (PD-1/PD-L1) inhibitors. CIP is one of the most therapy might be an option for patients with CIP, especially common fatal adverse events of PD-1/PD-L1 inhibitors (14). It has for those with poor response to steroid-based therapy. Further been reported that approximately 70% to 80% of CIP patients can studies are urgently needed to elucidate the detailed mechanism be controlled by routine corticosteroid treatment (15). One-week of combined regimen strategy to prevent and treat CIP. treatment of initial dosage of methylprednisolone (80mg/day) did not improve the patient’s clinical symptoms, indicating that CIP had a poor response to high-dose of methylprednisolone. The DATA AVAILABILITY STATEMENT patient was not sensitive to single agent corticosteroid, and thus fi thecourseofpulmonary brosis was not reversed. After that, we The original contributions presented in the study are included in attempted to add nintedanib to treat CIP. Thus, methylprednisolone the article/supplementary Material. Further inquiries can be (40 mg/day) plus nintedanib (150 mg bid) was administered. directed to the corresponding author. Unexpectedly, the improved general situation of the patient and the remitted clinal symptoms within 5 days indicated that pembrolizumab-associated pneumonitis had a favorable response to the combination therapy of methylprednisolone and nintedanib. ETHICS STATEMENT We decreased the dose of methylprednisolone by half dose because Written informed consent was obtained from the individual(s) we think the dosage of corticosteroid should be reduced after for the publication of any potentially identifiable images or data treatment has achieved remission of symptoms. The addition of included in this article. nintedanib to CIP treatment may reduce the dosage and even duration use of corticosteroid. In some practice, immune suppressants are recommended for CIP treatment (4, 15), but we did not try immunosuppressors such as mycophenolate mofetil and AUTHOR CONTRIBUTIONS cyclophosphamide for CIP treatment because they work slowly, which limits their use in CIP because of its acute or subacute course. X-HX treated the case and wrote the manuscript. H-YD, X-QL, Although there have never been trials of combination J-HW, ML, Z-HX, and Y-YQ treated the case. C-ZZ contributed treatment of ICIs and nintedanib until now, this combination to PET/CT response evaluation. All authors contributed to the therapy may prevent and treat CIP. To the best of our article and approved the submitted version. knowledge, this is the first report to provide clinical evidence for nintedanib in the treatment of earlier onset of ICI-induced CIP. One possible mechanism is nintedanib inhibits pulmonary FUNDING fibrosis by targeting VEGFR (16). Alternatively, nintedanib may reduce lung exudation and promote lung recovery through This study was supported by Beijing Xisike Clinical Oncology suppressing VEGF (17). The patient was administered Research Foundation (Y-XD2019-136, Y-2019Genecast-076).

Frontiers in Oncology | www.frontiersin.org 3 June 2021 | Volume 11 | Article 673877 Xie et al. Case Report: CIP Treated Successfully With Nintedanib

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